AU2020279253A1 - KRAS G12C inhibitors and uses thereof - Google Patents

Info

Publication number

AU2020279253A1

AU2020279253A1 AU2020279253A AU2020279253A AU2020279253A1 AU 2020279253 A1 AU2020279253 A1 AU 2020279253A1 AU 2020279253 A AU2020279253 A AU 2020279253A AU 2020279253 A AU2020279253 A AU 2020279253A AU 2020279253 A1 AU2020279253 A1 AU 2020279253A1

Authority

AU

Australia

Prior art keywords

compound

independently

proviso

alkyl

heteroatoms

Prior art date

2019-05-20

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• 102200006538 rs121913530 Human genes 0.000 title abstract description 30
• 239000003112 inhibitor Substances 0.000 title description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 373
• 150000003839 salts Chemical class 0.000 claims abstract description 133
• 238000000034 method Methods 0.000 claims abstract description 40
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
• 125000005842 heteroatom Chemical group 0.000 claims description 187
• 229910052760 oxygen Inorganic materials 0.000 claims description 164
• 125000000623 heterocyclic group Chemical group 0.000 claims description 152
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 132
• 229910052757 nitrogen Inorganic materials 0.000 claims description 121
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 119
• 125000003118 aryl group Chemical group 0.000 claims description 119
• 125000001072 heteroaryl group Chemical group 0.000 claims description 118
• 229910052731 fluorine Inorganic materials 0.000 claims description 112
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 109
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 109
• 229910052739 hydrogen Inorganic materials 0.000 claims description 97
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 85
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 83
• 229910052736 halogen Inorganic materials 0.000 claims description 82
• 150000002367 halogens Chemical class 0.000 claims description 82
• 229910052799 carbon Inorganic materials 0.000 claims description 77
• 229910052801 chlorine Inorganic materials 0.000 claims description 75
• 125000001188 haloalkyl group Chemical group 0.000 claims description 72
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 71
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 71
• -1 sulfolanyl Chemical group 0.000 claims description 68
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 67
• 125000003545 alkoxy group Chemical group 0.000 claims description 52
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 49
• 229910052717 sulfur Inorganic materials 0.000 claims description 48
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 44
• 229920006395 saturated elastomer Polymers 0.000 claims description 40
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
• 229910052794 bromium Inorganic materials 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 20
• 201000011510 cancer Diseases 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
• 125000002950 monocyclic group Chemical group 0.000 claims description 7
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
• 229940079593 drug Drugs 0.000 claims description 6
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 6
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 229940125904 compound 1 Drugs 0.000 claims description 4
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
• 241000283891 Kobus Species 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000004193 piperazinyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 2
• 125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 2
• HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 claims description 2
• 229940126639 Compound 33 Drugs 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 2
• 125000005458 thianyl group Chemical group 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 3
• PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims 1
• 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 claims 1
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims 1
• 230000001404 mediated effect Effects 0.000 abstract description 10
• 102100030708 GTPase KRas Human genes 0.000 abstract description 7
• 101000584612 Homo sapiens GTPase KRas Proteins 0.000 abstract description 7
• 230000035772 mutation Effects 0.000 abstract description 7
• 230000002401 inhibitory effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 293
• 239000000203 mixture Substances 0.000 description 275
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 204
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 171
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 156
• 235000019439 ethyl acetate Nutrition 0.000 description 142
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 126
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 126
• 239000000543 intermediate Substances 0.000 description 110
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
• 239000000741 silica gel Substances 0.000 description 98
• 229910002027 silica gel Inorganic materials 0.000 description 98
• 239000007832 Na2SO4 Substances 0.000 description 93
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 93
• 229910052938 sodium sulfate Inorganic materials 0.000 description 93
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
• 239000000243 solution Substances 0.000 description 84
• 230000015572 biosynthetic process Effects 0.000 description 81
• 238000003786 synthesis reaction Methods 0.000 description 81
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
• 238000005160 1H NMR spectroscopy Methods 0.000 description 72
• 239000012267 brine Substances 0.000 description 69
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 69
• 238000006243 chemical reaction Methods 0.000 description 66
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 64
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 61
• 238000003818 flash chromatography Methods 0.000 description 59
• 238000000746 purification Methods 0.000 description 56
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
• 239000000284 extract Substances 0.000 description 54
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 49
• 235000011152 sodium sulphate Nutrition 0.000 description 49
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
• 239000007787 solid Substances 0.000 description 39
• 125000001424 substituent group Chemical group 0.000 description 35
• 210000004027 cell Anatomy 0.000 description 34
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
• 229910000027 potassium carbonate Inorganic materials 0.000 description 32
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 238000002953 preparative HPLC Methods 0.000 description 30
• 239000006260 foam Substances 0.000 description 29
• WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 28
• 125000000217 alkyl group Chemical group 0.000 description 27
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 26
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 26
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 239000000047 product Substances 0.000 description 22
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
• 125000004429 atom Chemical group 0.000 description 20
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 20
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 19
• 201000010099 disease Diseases 0.000 description 18
• 239000003921 oil Substances 0.000 description 16
• 235000019198 oils Nutrition 0.000 description 16
• VCOJPHPOVDIRJK-LURJTMIESA-N [(2s)-1-methylpyrrolidin-2-yl]methanol Chemical compound CN1CCC[C@H]1CO VCOJPHPOVDIRJK-LURJTMIESA-N 0.000 description 15
• 235000015320 potassium carbonate Nutrition 0.000 description 15
• ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 15
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
• 238000011282 treatment Methods 0.000 description 14
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
• 125000002619 bicyclic group Chemical group 0.000 description 12
• 239000001257 hydrogen Substances 0.000 description 12
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 12
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 12
• NSXYMCIOCLLWFZ-UHFFFAOYSA-N 2-fluoroprop-2-enoyl 2-fluoroprop-2-enoate Chemical compound FC(=C)C(=O)OC(=O)C(F)=C NSXYMCIOCLLWFZ-UHFFFAOYSA-N 0.000 description 11
• 235000019270 ammonium chloride Nutrition 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• 125000001183 hydrocarbyl group Chemical group 0.000 description 11
• 239000012074 organic phase Substances 0.000 description 11
• 238000002360 preparation method Methods 0.000 description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
• 229910006124 SOCl2 Inorganic materials 0.000 description 10
• 239000012043 crude product Substances 0.000 description 10
• JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 10
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
• 239000000651 prodrug Substances 0.000 description 10
• 229940002612 prodrug Drugs 0.000 description 10
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 10
• 239000003054 catalyst Substances 0.000 description 9
• 238000001816 cooling Methods 0.000 description 9
• 239000000126 substance Substances 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
• FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 8
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• 239000002253 acid Substances 0.000 description 8
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• 208000035475 disorder Diseases 0.000 description 8
• 150000002576 ketones Chemical class 0.000 description 8
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• 239000002904 solvent Substances 0.000 description 8
• 125000003342 alkenyl group Chemical group 0.000 description 7
• AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 7
• 229910000162 sodium phosphate Inorganic materials 0.000 description 7
• 125000000547 substituted alkyl group Chemical group 0.000 description 7
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
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• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
• 229910019891 RuCl3 Inorganic materials 0.000 description 6
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
• 150000001721 carbon Chemical group 0.000 description 6
• 238000004440 column chromatography Methods 0.000 description 6
• 125000004122 cyclic group Chemical group 0.000 description 6
• 125000000392 cycloalkenyl group Chemical group 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 6
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• YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 6
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• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 6
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• 238000006467 substitution reaction Methods 0.000 description 6
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• 208000001333 Colorectal Neoplasms Diseases 0.000 description 5
• 125000000304 alkynyl group Chemical group 0.000 description 5
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• RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 5
• 125000006239 protecting group Chemical group 0.000 description 5
• 239000007858 starting material Substances 0.000 description 5
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• 238000004293 19F NMR spectroscopy Methods 0.000 description 4
• KBAXPKVNVXMVKV-UHFFFAOYSA-N 2,4-dichloro-5,6,7,8-tetrahydroquinazoline Chemical compound C1CCCC2=NC(Cl)=NC(Cl)=C21 KBAXPKVNVXMVKV-UHFFFAOYSA-N 0.000 description 4
• COVOQJOFHIWADC-UHFFFAOYSA-N 2,4-dichloro-6,7-dihydro-5H-quinazolin-8-one Chemical compound ClC1=NC(=NC=2C(CCCC1=2)=O)Cl COVOQJOFHIWADC-UHFFFAOYSA-N 0.000 description 4
• YRYQLVCTQFBRLD-UIOOFZCWSA-N 2-[(2S)-4-[7-(8-methylnaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoylpiperazin-2-yl]acetonitrile Chemical compound C(C=C)(=O)N1[C@H](CN(CC1)C=1C2=C(N=C(N=1)OC[C@H]1N(CCC1)C)CN(CC2)C1=CC=CC2=CC=CC(=C12)C)CC#N YRYQLVCTQFBRLD-UIOOFZCWSA-N 0.000 description 4
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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• 210000003932 urinary bladder Anatomy 0.000 description 1
• 239000003643 water by type Substances 0.000 description 1